The Role of Efferocytosis in Inflammatory Arthritis

胞吞作用在炎症性关节炎中的作用

• 批准号: 10572853
• 负责人: Sanja Arandjelovic
• 金额: $ 24.23万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-14 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572853
• 关键词: ANXA5 gene; Ablation; Affect; Animal Model; Anti-Inflammatory Agents; Apoptosis; Apoptotic; Arthritis; BAI1 gene; Binding; Cell Death; Cells; Cytoskeleton; Data; Deterioration; Development; Digestion; Disease; Eating; Environment; Excision; Failure; Genetic; Health; Homeostasis; Human; Infection; Inflammation; Inflammation Mediators; Inflammatory Arthritis; Inflammatory Response; Injections; Joints; Knowledge; Link; Lysosomes; MERTK gene; Mediating; Membrane Lipids; Metabolic; Modeling; Mus; Nucleotides; Organism; Pathology; Patients; Persons; Phagocytes; Phagocytosis; Phagosomes; Phosphatidylserines; Play; Process; Resolution; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Synovial joint; Testing; Therapeutic; Tissues; Transgenic Mice; chemokine; chronic inflammatory disease; joint inflammation; metabolomics; mouse model; overexpression; pharmacologic; phosphatidylserine receptor; prevent; receptor; response; therapy design

THE ROLE OF EFFEROCYTOSIS IN INFLAMMATORY ARTHRITIS Abstract Rheumatoid arthritis (RA) is a chronic inflammatory disease of the synovial joints which affects 1 in 100 people globally and millions in the US alone. We noted marked presence of apoptotic cells in the inflamed joints of arthritic mice. Apoptosis is intricately linked with phagocytosis of apoptotic cells, also known as ‘efferocytosis’. The current dogma suggests that increased apoptotic cell persistence in tissues inevitably leads to pathology. However, our data presented in this application suggest that this dogma warrants further testing. First, we show that systemic injection of apoptotic cells effectively alleviates inflammation in arthritic mice. Further, cell-free apoptotic cell supernatants or even purified apoptotic cell-released metabolites potently suppress inflammatory arthritis. Finally, pharmacologic or genetic efferocytosis reduction (not complete ablation) also reduce inflammation in arthritic mice. Here, we will test the hypothesis that reduced efferocytosis alleviates inflammation in arthritis through increased release of anti-inflammatory mediators (from uncleared apoptotic cells) and enhanced corpse processing/degradation (due to reduced corpse load in phagocytes). We will pursue the following aims: 1. Using mice with pharmacologic or genetic decrease in efferocytosis, we will quantify multiple disease parameters in arthritis, determine the numbers of apoptotic cells in the inflamed joints, analyze the phagocyte response, and analyze the metabolomics of reduced cell clearance environments. 2. Generate and validate a new transgenic mouse model with tissue-specific, inducible reduction of efferocytosis. Our findings will further our understanding of efferocytosis in homeostasis and inflammation and could open new avenues in therapeutic designs for the treatment of rheumatoid arthritis.

红细胞增多症在炎症性关节炎中的作用 摘要 类风湿关节炎(RA)是一种慢性滑膜关节炎症性疾病，每100人中就有1人患病 在全球范围内，仅美国就有数百万人。我们注意到在发炎的关节中有明显的凋亡细胞。 关节炎小鼠。细胞凋亡与凋亡细胞的吞噬作用密切相关，也称为“胞吐作用”。 目前的教条表明，组织中不断增加的凋亡细胞不可避免地导致了病理。 然而，我们在这份申请中提供的数据表明，这一教条值得进一步测试。首先，我们展示 全身注射凋亡细胞有效地减轻了关节炎小鼠的炎症。此外，无细胞的 凋亡细胞上清液甚至纯化的凋亡细胞释放的代谢物有效地抑制炎症 关节炎。最后，药物或遗传性泡沫化减少(不完全消融)也会减少。 关节炎小鼠的炎症反应。在这里，我们将检验减少泡泡吞噬作用可以减轻炎症的假设。 在关节炎中，通过增加抗炎介质的释放(来自未清除的凋亡细胞)和 增强身体处理/降解能力(由于吞噬细胞中的身体负荷减少)。我们会继续推行 以下目标：1.利用药物或遗传性泡出减少的小鼠，我们将量化多个 关节炎的疾病参数，测定炎症关节中的凋亡细胞数量，分析 吞噬细胞反应，并分析减少细胞清除环境的代谢组学。2.生成和 验证一种新的转基因小鼠模型，该模型具有组织特异性的、可诱导的减少胞吐作用。我们的发现 将进一步加深我们对体内稳态和炎症中的胞吐作用的理解，并可能在 治疗类风湿性关节炎的治疗设计。